Carcinoma of the colon is a major cause of cancer deaths in this country, and the pathogenic factors leading to its development have not been identified. We have developed techniques to study abnormalities of cellular proliferation in the colonic mucosa of subjects with diseases carrying a high risk of developing carcinoma of the colon, i.e., ulcerative colitis, polyposis or a previous resection of a colonic carcinoma. In previous studies we showed that thymidine kinase (TK), an enzyme associated with proliferating cells, is highest in the proliferative zone of colon mucosa (deep crypt zone), and falls off rapidly as the cells migrate upward to the luminal surface (mature cell zone). In the surfaces of polyps and carcinoma, a raised amount of thymidine kinase was found suggesting a loss of normal regulatory control mechanisms. These studies were confined to surgically resected colonic tissue. We have now developed a technique to carry out these studies on rectal biopsies, thereby expanding the population available for study to include even out-patients. Objective: we will measure the gradient of TK (and other nucleic acid enzymes) in rectal biopsies from normal mucosa and in mucosa of patients with "high risk" disease. Half-yearly study of rectal biopsy enzyme gradients will be done, and patients followed for a period of 3 years. Lack of sharp gradients will be sought as prospective evidence that the mucosa is indeed premalignant. Methods: the biopsy tissue will be frozen on a cryostat chuck and the mucosa will be separated into mature, proliferative, and "transitional" zones. Enzymes will be measured on homogenates of the sectioned tissue of controls and patients in each of the the 3 high risk groups. Microauto-radiographic localization of DNA synthesis will be studied for comparison in in vitro organ cultures of adjacent rectal mucosa by incubation with tritriated thymidine. Abnormal localization of DNA synthesis, e.g. in surface epithelium, is presently the best indication of a proliferative disorder, but takes 6-8 weeks for results, as compared to 1-2 days for these enzyme measurements.